The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.

Fernandez-Rojo, Manuel A; Pearen, Michael A; Burgess, Anita G; Ikonomopoulou, Maria P; Hoang-Le, Diem; Genz, Berit; Saggiomo, Silvia L; Nawaratna, Sujeevi S K; Poli, Maura; Reissmann, Regina; Gobert, Geoffrey N; Deutsch, Urban; Engelhardt, Britta; Brooks, Andrew J; Jones, Alun; Arosio, Paolo; Ramm, Grant A (2024). The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation. Science signaling, 17(830) American Association for the Advancement of Science 10.1126/scisignal.ade4335

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Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule-1 (ICAM-1). FTH-ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH-ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1-/- or Nlrp3-/- mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Sahli Building > Forschungsgruppe Neurologie
UniBE Contributor:	Reissmann, Regina, Deutsch, Urban, Engelhardt, Britta
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1937-9145
Publisher:	American Association for the Advancement of Science
Language:	English
Submitter:	Pubmed Import
Date Deposited:	03 Apr 2024 14:51
Last Modified:	03 Apr 2024 14:51
Publisher DOI:	10.1126/scisignal.ade4335
PubMed ID:	38564492
URI:	https://boris.unibe.ch/id/eprint/195553